Apolipoprotein D (Apo D) is a glycoprotein belonging to the lipocalin family and it was initially isolated from human plasma high density lipoproteins (McConathy and Alaupovic, 1973). As other lipocalins, Apo D shows a β-barrel tertiary structure and transports small hydrophobic ligands like arachidonic acid, cholesterol, bilirubin, or steroids (Rassart et al., 2000). It is expressed, in a wide variety of mammalian tissues like pancreas, placenta, spleen, adrenal gland, lungs, and brain (Bishop et al., 1995 and Boyles et al., 1990; Provost et al., 1990 and Provost et al., 1995; Seguin et al., 1995 and Smith et al., 1990), and in nonmammalian like chicken, Drosophila melanogaster, or Escherichia coli ( Bishop et al., 1995, Ganfornina et al., 2005 and Sanchez et al., 2000). Its expression can be regulated by several conditions. In this sense, it has been shown that its promoter has different responsive elements to estrogens, stress, acute phase, androgens, etc. ( Lambert et al., 1993). Due to the wide distribution of Apo D messenger ribonucleic acid (mRNA) and the variety of functions that are attributed to the protein, it is considered as multifunctional.
In the peripheral nervous system (PNS), Apo D is synthesized by endoneural fibroblasts and its expression is increased following a lesion. It has been shown that Apo D protein and mRNA increase, 500- and 40-fold respectively, in peripheral nerves during regeneration. Thus, a possible role of Apo D in lipid binding and transport that take place in renervation, in association with other apolipoproteins, has been suggested (Spreyer et al., 1990).
In the central nervous system (CNS), it is localized in oligodendrocytes, astrocytes, neurons, and perivascular cells (Hu et al., 2001 and Navarro et al., 1998). A difference in staining patterns between glia and neurons has been observed in human brain regions (Hu et al., 2001 and Navarro et al., 1998). Northern blot analysis of total mRNA extracts from gray and white matter of human and rabbit brains showed that white matter is the main site of Apo D gene expression (Provost et al., 1991). Furthermore, some studies have reported Apo D mRNA in neurons, neuroglia, and perivascular cells by in situ hybridization (Belloir et al., 2001 and Navarro et al., 2010; Sanchez et al., 2002 and Smith et al., 1990).
Apo D expression is up regulated in several neuropathological conditions, after traumatic brain injury and during development and aging (Navarro et al., 2010 and Rassart et al., 2000). In fact, an increase in Apo D levels has been shown in Alzheimer's disease (AD) (Belloir et al., 2001 and Glockner and Ohm, 2003; Terrisse et al., 1998 and Thomas et al., 2003). Moreover, in schizophrenia, characterized by a lipidic disrupt, Apo D is upregulated (Thomas et al., 2001). Increased levels of Apo D have also been found in the brains of Niemann-Pick type C disease mice, which have a lysosomal cholesterol disorder that is associated with defects in cellular cholesterol homeostasis and progressive neurodegeneration (Suresh et al., 1998). A specific induction of Apo D was also observed in kainic acid-lesioned rat hippocampus (Ong et al., 1997) and increased levels of Apo D have been found during development and aging, where an important neuronal loss takes place (Kalman et al., 2000, Navarro et al., 2010 and Sanchez et al., 2002). Thus, a relationship between neuronal degeneration and Apo D expression may exist. However, the role played by the protein is still unknown. In our previous works, we found that dopaminergic neurons of substantia nigra are unable to express Apo D; this could explain its vulnerability (Ordoñez et al., 2006). Moreover, we previously analyzed the expression of Apo D in relationship with damaged neurons in various regions of human brains from patients without any neurological or psychological disorders and we found that injured neurons are always immunonegative for Apo D (Navarro et al., 2008). Taking together, these results led us to propose a neuroprotective role for Apo D.
On the other hand, studies have shown sexual dimorphism in the aging brain. Age-related hormonal changes that occur in men and women are very different, and it is proved their influence in AD risk (Brann et al., 2007). The female menopause results in a dramatic reduction of estrogen and progesterone levels, which accelerates the cognitive decline. Several studies have provided evidence of neurotrophic, antioxidant, and anti-inflammatory properties of estrogens, demonstrating a possible mechanism for protection against AD (Brinton, 2004). It has been observed that estrogens can slow the progression of neurodegenerative diseases once these have been manifested. Some studies show that administration of hormone replacement therapy in postmenopausal women reduces the risk of manifestation of AD or, at least, delays the progression of symptoms (Brann et al., 2007). In this sense, Apo D shows 3 estrogen-responsive elements in its promoter so its expression could be modulated by these hormones and be partly responsible for estrogen's neuroprotective role.
The aim of this work is to study possible gender differences in Apo D expression in aging and AD. We have found that only women show an increase of Apo D with age while, both men and women show this feature during Braak stages progression in AD.
